This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cortactin is a cortical actin-binding protein and substrate for various tumor-promoting oncogenic kinases. Cortactin interacts with the actin-related (Arp) 2/3 protein complex, which drives cell motility by initiating and maintaining polymerization of actin filaments at the leading edge of motile cells. Cortactin is overexpressed in several human cancers, most frequently in head and neck squamous cell carcinoma (HNSCC) as a result of amplification of chromosome 11q13. HNSCC is the most common cancer that afflicts the oral cavity and associated tissues, and follows a well-defined paradigm of progression from hyperplasia to carcinoma. Recent work from our laboratory has demonstrated that cortactin overexpression directly modulates HNSCC motility and invasion by enhanced activation of Arp2/3 complex and by tyrosine phosphorylation mediated by Src-family kinases. These studies suggest that cortactin overexpression plays a direct role in HNSCC invasion and metastasis. However, the precise stage in HNSCC that cortactin is overexpressed, the suitability of cortactin as a prognostic marker for HNSCC invasion, the molecules cortactin associates with and the influence of cortactin overexpression in HNSCC progression have not been investigated. This proposal will address these questions through three aims: Aim 1 will determinine the stage(s) during HNSCC progression in which the cortactin locus is amplified, and the protein overexpressed/phosphorylated on tyrosine and serine residues. Aim 2 will identify proteins that interact with cortactin in HNSCC cells +/- chromosome 11q13 amplification by proteomic methods. Aim 3 will develop a transgenic mouse model of cortactin in oral cancer to evaluate how cortactin influences HNSCC development and progression.